TW201713325A - Ophthalmic solution and method for maintaining preservative efficacy of ophthalmic solution - Google Patents

Abstract

Provided are an ophthalmic solution, which can maintain excellent preservative efficacy over a long period of time in spite of being substantially free from a cationic preservative or a nonionic surfactant, and a method for maintaining the preservative efficacy of an ophthalmic solution. An ophthalmic solution which contains 0.01-1.0% (w/v) of 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a salt thereof, 215-360 mM of borate ion and 0.001-0.15% (w/v) of sodium edetate and is substantially free from a cationic preservative or a nonionic surfactant, said ophthalmic solution having an osmotic pressure ratio of 0.8-1.3. An ophthalmic solution which contains 0.01-1.0% (w/v) of 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a salt thereof, 215-360 mM of borate ion and 0.001-0.15% (w/v) of sodium edetate and is substantially free from a cationic preservative or a nonionic surfactant, said ophthalmic solution complies with the decision criteria in the preservation efficacy test in The Japanese Pharmacopoeia, Sixteenth Edition.

Description

Eye drop and eye drop antiseptic effect maintenance method

The present invention relates to a method for maintaining the efficacy of eye drops and eye drops.

Bromfenac sodium has a therapeutic effect on the biosynthesis of prostaglandin (PG), and has therapeutic effects on conjunctivitis, allergic conjunctivitis, or orbital inflammation associated with ocular inflammation, and is generally widely used as an eye drop.

Conventionally, a cationic preservative such as benzalkonium chloride has been widely known as a preservative in eye drops (for example, Patent Document 1 and Patent Document 2). Further, in the eye drop, a nonionic surfactant which does not exhibit ionicity even when dissolved in water is generally used.

[Patent Document 1] Japanese Patent Laid-Open No. 2-124817

[Patent Document 2] International Publication No. 2014/078766

As described in Patent Document 1 and Patent Document 2, it is known that when a bromfenac sodium is used together with a cationic preservative, a red insoluble foreign matter is precipitated. Also, if you use eye drops When the cationic preservative is blended at a high concentration, the keratinous protein is denatured, and the cornea or conjunctival epithelium is peeled off or damaged.

Therefore, it is preferred to reduce the use concentration of the cationic preservative as much as possible, and it is preferred to use no cationic preservative at all, but this causes a problem of lack of antiseptic effect.

On the other hand, regarding the eye drop, the surface tension of the eye drops is lowered by blending the nonionic surfactant. As a result, there is a problem that dripping liquid of the eye drops or cracking of the eye container.

From the viewpoint of preventing dripping of the eye drops and preventing cracking of the eye container, it is preferable to reduce the use concentration of the nonionic surfactant as much as possible, and it is preferable to use no nonionic surfactant at all. .

An object of the present invention is to provide an eye drop which can maintain excellent antiseptic efficacy for a long period of time without substantially containing a cationic preservative and a nonionic surfactant, and a method for maintaining the antiseptic effect of an eye drop.

The present inventors have found that if a boric acid ion and a sodium edetate in a specific concentration range are contained in an eye drop containing bromfenac sodium, the cationic preservative and the nonionic interface are substantially not contained. The active agent is also capable of maintaining excellent antiseptic efficacy for a long period of time, thereby completing the present invention. That is, the present invention is as follows.

[1] A first aspect of the present invention is an eye drop comprising 0.01 to 1.0% (w/v) of 2-amino-3-(4-bromobenzylidene)phenylacetic acid or a salt thereof, 215-360 mM boric acid ion and 0.001-0.15% (w/v) sodium edetate substantially do not contain a cationic preservative and a nonionic surfactant, and the osmotic pressure ratio is 0.8 to 1.3.

[2] A second aspect of the present invention is an eye drop comprising 0.01 to 1.0% (w/v) of 2-amino-3-(4-bromobenzylidene)phenylacetic acid or a salt thereof, 215-360 mM boric acid ion and 0.001-0.15% (w/v) sodium edetate, substantially free of cationic preservatives and nonionic surfactants, and which comply with the preservation of the 16th revised edition of the Japanese Pharmacopoeia The criterion for judgment in the efficacy test method.

[3] The ophthalmic agent according to [1] or [2] wherein the 2-amino-3-(4-bromobenzylidene) phenylacetic acid or a salt thereof is bromfenac sodium.

[4] The eye drop according to any one of [1] to [3] further comprising 0.1 to 0.3% (w/v) of sodium chloride.

[5] The eye drop agent according to any one of [1] to [4] wherein the pH is from 7.8 to 8.6.

[6] The eye drop agent according to any one of [1] to [5], which is contained in a multi-dose type container.

[7] A method for maintaining the antiseptic effect of an eye drop, which is a method for maintaining the antiseptic effect of an eye drop containing 0.01 to 1.0% (w/v) of 2-amino-3- (4-bromobenzylidene) phenylacetic acid or a salt thereof, and substantially free of a cationic preservative and a nonionic surfactant; the above method comprises: causing the above eyedrop to contain boric acid ions of 215 to 360 mM and Sodium 0.001 to 0.15% (w/v), and the osmotic pressure ratio of the above eye drops is set to 0.8 to 1.3.

According to the present invention, a bromfenac eye drop containing a boric acid ion and sodium edetate in a specific concentration range and substantially containing no cationic preservative and a nonionic surfactant can exhibit excellent antiseptic efficacy for a long period of time. Further, the bromfenac eyedrop of the present invention is substantially free There are cationic preservatives such as benzalkonium chloride and nonionic surfactants, so there is no need to worry about damage to corneal cells, and no dripping of eye drops or cracks in the eye container.

Hereinafter, embodiments of the present invention will be described.

The ophthalmic agent of the present invention contains 0.01 to 1.0% (w/v) of 2-amino-3-(4-bromobenzylidene)phenylacetic acid or a salt thereof, 215 to 360 mM of boric acid ion and 0.001 to 0.15. % (w/v) sodium edetate, and substantially does not contain a cationic preservative and a nonionic surfactant.

Bromfenic acid or its salt

The ophthalmic agent of the present embodiment contains 2-amino-3-(4-bromobenzylidene)phenylacetic acid (also referred to as "bromofenic acid") or a salt thereof as a medicinal ingredient, preferably only 2 -Amino-3-(4-bromobenzylidene)phenylacetic acid or a salt thereof as a medicinal ingredient. In the eye drop of the present embodiment, 2-amino-3-(4-bromobenzylidene)phenylacetic acid or a salt thereof is selected from the group consisting of non-dissociated 2-amino-3-(4-bromobenzyl) Mercapto) itself, a salt of 2-amino-3-(4-bromobenzylidene)phenylacetic acid, an amphoteric ion (a carboxyl group forms a carboxylate ion, and an amine group forms an ammonium ion), a positive ion body At least one of the group consisting of (only the amine group forms an ammonium ion) and the negative ion body (only the carboxyl group forms a carboxylate ion), and can exist in a dissolved form, preferably 2-amino-3-(4) a salt of -bromobenzhydryl)phenylacetic acid.

In the eye drop of the present embodiment, the salt of 2-amino-3-(4-bromobenzylidene)phenylacetic acid is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples of the salt include: A salt with an inorganic acid, a salt with an organic acid, a quaternary ammonium salt, a salt with a halogen ion, a salt with an alkali metal, a salt with an alkaline earth metal, a metal salt, a salt with an organic amine, or the like. The salt with the inorganic acid may, for example, be a salt of hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid or phosphoric acid. Examples of the salt with an organic acid include acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptonic acid, glucuronic acid, and p-benzoic acid. Formic acid, methanesulfonic acid, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, lactobionic acid, oleic acid, pamoic acid, polygalacturonic acid, stearic acid, citric acid, a salt of trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, sulfosalicylic acid or the like. The quaternary ammonium salt may, for example, be a salt with methyl bromide or methyl iodide. Examples of the salt with a halogen ion include a salt with a chloride ion, a bromide ion, and an iodide ion. Examples of the salt with an alkali metal include a salt of lithium, sodium, potassium, or the like, and a salt with an alkaline earth metal. Examples thereof include salts with calcium, magnesium, and the like. Examples of the metal salt include salts with iron, zinc, and the like. Examples of the salt with an organic amine include tri-ethylenediamine, 2-aminoethanol, 2,2-imidobis(ethanol), and 1-deoxy-1-(methylamino)-2. -D-sorbitol (1-deoxy-1-(methylamino)-2-D-sorbitol), 2-amino-2-(hydroxymethyl)-1,3-propanediol, procaine, N, N a salt of bis(phenylmethyl)-1,2-ethanediamine or the like. In the eye drop of the present embodiment, a preferred salt of 2-amino-3-(4-bromobenzylidene)phenylacetic acid is a sodium salt.

In the eye drops of the present embodiment, the concentration of 2-amino-3-(4-bromobenzylidene)phenylacetic acid or a salt thereof is not sufficient as long as it is sufficient for exerting the desired pharmacological effect. It is particularly limited, preferably 0.01 to 1.0% (w/v), more preferably 0.03 to 0.5% (w/v), further preferably 0.05 to 0.2% (w/v), and most preferably 0.08 to 0.1%. (w/v). Furthermore, with regard to the concentrations, In the case of using a salt of 2-amino-3-(4-bromobenzylidene)phenylacetic acid or a hydrate thereof, the conversion to 2-amino-3-(4-bromobenzylidene) is used. The quality of phenylacetic acid is calculated.

Boric acid ion

The boric acid ion can be contained in the eye drop of the present embodiment by blending a compound which is dissolved in water to produce boric acid ions. The compound is not particularly limited, and is preferably boric acid and/or borate, and more preferably boric acid and borate are used. Examples of the borate include borax, sodium borate, potassium borate, and the like, and borax is preferred.

In the eye drop of the present embodiment, when the boric acid ion concentration is 215 mM or more, the preservative effect is excellent, and when it is 360 mM or less, no crystal of boric acid is precipitated. The boric acid ion concentration in the eye drop of the present embodiment is preferably 217 mM, more preferably 219 mM, and the upper limit is preferably 340 mM, more preferably 310 mM, still more preferably 307 mM.

Sodium edetate

The sodium edetate (sodium salt of ethylenediaminetetraacetic acid) in the eye drop of the present embodiment may also be in the form of a hydrate. Examples of the sodium edetate include edetic acid-sodium, disodium edetate, and tetrasodium edetate. Examples of the hydrate include dihydrate of disodium edetate.

When the concentration of sodium edetate of the eye drop agent of the present embodiment is 0.001% (w/v) or more, the antiseptic effect is excellent, and in particular, the antiseptic effect against Escherichia coli (E. coli) and/or Pseudomonas aeruginosa is excellent. If it is 0.15% (w/v) or less, it will not cause irritation. The boric acid ion concentration in the eye drop of the present embodiment is preferably 0.005% (w/v), more preferably 0.01% (w/v), still more preferably 0.02% (w/v). The upper limit is preferably 0.13% (w/v), more preferably 0.1% (w/v), still more preferably 0.08% (w/v). The eye drop agent of the present embodiment contains sodium edetate and boric acid ions in a concentration within the above numerical range, and thus Synergistically exert excellent antiseptic properties.

Cationic preservative, nonionic surfactant

The eye drop agent of the present embodiment does not substantially contain a cationic preservative and a nonionic surfactant. In the eyedrops of the present embodiment, the term "substantially no cationic preservative" means that the concentration of the cationic preservative in the eye drops is 0.003% (w/v) or less, preferably 0.001% (w). /v) Hereinafter, it is more preferable that the cationic preservative is not contained at all. In the eyedrops of the present embodiment, the term "substantially no nonionic surfactant" means that the concentration of the nonionic surfactant in the eyedrops is 0.003% (w/v) or less, preferably. It is 0.001% (w/v) or less, and further preferably contains no nonionic surfactant at all.

Specifically, the ophthalmic agent of the present embodiment does not substantially contain a cationic preservative such as loceceptine, bensinin chloride, cetylpyridinium chloride or cetyltrimethylammonium bromide, and is substantially Does not contain polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 60 and other polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan monopalmitate (polyoxyethylene sorbitan monopalmitate), polyoxyethylene sorbitan monolauric A nonionic surfactant such as polyoxyethylene sorbitol such as an acid ester.

Since the eye drop agent of the present embodiment does not substantially contain the cationic preservative, it is not necessary to worry about damage to the corneal cells, and since the nonionic surfactant is not substantially contained, the eye drops are not generated. The liquid droplets or the cracks in the eye container can suppress the generation of fine particles in the eye drops.

Sodium chloride

In the case where the eyedrops of the present embodiment contain sodium chloride, the concentration thereof is preferably 0.01% (w/v), more preferably 0.05% (w/v), and still more preferably 0.1% (w/v), The upper limit is preferably 0.5% (w/v), more preferably 0.3% (w/v). In the eye drop of the present embodiment, when the sodium chloride concentration is within the above numerical range, the concentration of boric acid ions is also determined, but the osmotic pressure ratio of the eye drop agent is easily adjusted within the above numerical range, and it is difficult to precipitate boric acid. , and easy to play an excellent antiseptic effect.

Other additives

In order to adjust the pH to the preferred range described below, the eye drop of the present embodiment further preferably contains a pH adjuster. The pH adjuster is not particularly limited as long as it can adjust the pH of the eye drop of the present embodiment, and specific examples thereof include dilute hydrochloric acid and sodium hydroxide. The addition amount (concentration) of the pH adjuster is not particularly limited as long as the pH of the eye drop of the present embodiment can be adjusted to the preferred range described below.

The eye drop of the present embodiment may further contain a buffering agent in order to adjust the pH to the preferred range described below. Examples of the buffering agent include ε-aminohexanoic acid, sodium phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, and sodium acetate. The addition amount (concentration) of the buffering agent is not particularly limited as long as the pH of the eyedropting agent of the present embodiment can be adjusted to the preferred range described below.

The ophthalmic agent of the present embodiment does not substantially contain a cationic preservative, but may be contained as long as it is a preservative for a pharmaceutical preservative, and the concentration thereof is, for example, preferably 0.002. % (w/v) or less, more preferably 0.0015% (w/v) or less. However, since the eyedrops of the present embodiment contain boric acid ions and sodium edetate in a specific concentration range as described above, it is not necessary to contain a "preservative other than a cationic preservative", and it is preferable not to contain "cationic antiseptic". Preservatives other than agents".

Further, the eyedrop agent of the present embodiment does not substantially contain a nonionic surfactant, but may be used as a pharmaceutical agent as long as it is a surfactant other than a nonionic surfactant. The surfactant of the additive may contain, for example, a cationic surfactant or an anionic surfactant.

Examples of the cationic surfactant include an alkylamine salt, an alkylamine polyoxyethylene adduct, a fatty acid triethanolamine monoester salt, a guanylaminoethylamine salt, a fatty acid polyamine condensate, and an alkane. Imidazolinium, 1-nonylamino-2-alkylimidazoline, 1-hydroxyethyl-2-alkylimidazoline, and the like.

Examples of the anionic surfactant include phospholipids and the like, and examples of the phospholipid include lecithin.

However, since the eyedrops of the present embodiment contain boric acid ions and sodium edetate in a specific concentration range as described above, it is not necessary to contain a "surfactant other than the nonionic surfactant", and it is preferable not to contain " A surfactant other than a nonionic surfactant."

Eye drop

The eye drop agent of the present embodiment is preferably an aqueous composition. In the present embodiment, the "aqueous composition" means a composition containing water as a base. The eye drop of the present embodiment preferably contains at least the above 2-amino-3-(4-bromobenzylidene)phenylacetic acid or a salt thereof, boric acid ion, and sodium edetate as the aqueous composition. For the aqueous solution, for example, the following eye drops can be used as the eye drops.

In the eye drops of the present embodiment, a pharmaceutically acceptable additive may be added as needed.

When the pH of the eye drop agent of the present embodiment is used as a medicinal ingredient in the case of using a salt of bromfenac, the lower limit is preferably 7.8, more preferably in terms of dissolving the salt sufficiently. Is 8.0. Further, the pH of the eye drop agent is not irritating to the eye, and the upper limit is preferably 8.6, more preferably 8.3. When bromide acid itself is used as a medicinal ingredient, It is preferably a pH within the above numerical range.

In the first aspect of the present embodiment, the eye drop agent of the present embodiment has an osmotic pressure ratio of 0.8 to 1.3. Further, the osmotic pressure ratio is determined by the method described in the osmotic pressure measuring method (osmotic concentration measuring method) of the 16th revised edition of the Japanese Pharmacopoeia, specifically, the osmotic concentration ( c _S ) of the physiological saline is fixed ( When the osmotic concentration ( c _T ) of the eye drop of the present embodiment is measured, the osmotic pressure ratio of the eye drop of the present embodiment can be calculated by the following formula.

Osmotic pressure ratio = c _T / c _S

When the osmotic pressure ratio of the eye drop agent of the present embodiment is within the above range, boric acid is hardly precipitated, and it is easy to exhibit excellent antiseptic effect. The osmotic pressure ratio in the eye drop of the present embodiment is preferably 0.80, more preferably 0.86, still more preferably 1.05, and the upper limit is preferably 1.25, more preferably 1.23, and further preferably Good is 1.21, and even better is 1.20. In the eye drops of the second aspect of the present embodiment described below, the osmotic pressure ratio is also preferably in the above numerical range. In the eye drops of the present embodiment, the osmotic pressure ratio is considered to be a balance between a salt concentration such as sodium chloride or potassium chloride, a boric acid ion concentration, a pH adjusting agent, a buffering agent, and the like.

In the second aspect of the present embodiment, the eyedrop of the present embodiment conforms to the criteria for determination in the preservation efficacy test method of the sixteenth revised edition of the Japanese Pharmacopoeia. In the present embodiment, the criteria used in the following examples are applied as the criterion for determination. The eyedrops of the second aspect of the present embodiment are not only against Staphylococcus aureus, Candidaalbicans, and Aspergillus brasiliensis, but also strong in need of this criterion. Escherichia coli and Pseudomonas aeruginosa, which have the usual preservative efficacy, are preserved for 2 weeks and 4 weeks in accordance with the criteria for preservation. In this specification, the preservation effect determined by the above-mentioned preservation efficacy test method is also referred to as Antiseptic effect. It is also preferred that the eyedrops in the first aspect of the embodiment have a preservation effect in accordance with the above criteria.

The ophthalmic agent of the present embodiment can be prepared, for example, by a usual method, for example, 2-amino-3-(4-bromobenzylidene)phenylacetic acid or a salt thereof, boric acid ion and sodium edetate, and The sodium chloride, potassium chloride, a buffer, and the like to be blended are dissolved in water, and if necessary, a pH adjuster or the like is added to adjust the pH.

In the preparation of the eyedrops of the present embodiment, in addition to 2-amino-3-(4-bromobenzylidene)phenylacetic acid or a salt thereof, a hydrate thereof may be used. Specific examples of the hydrate include sodium 2-amino-3-(4-bromobenzylidene)phenylacetate. Mono/dihydrate, sodium 2-amino-3-(4-bromobenzylidene)phenylacetate. Monohydrate, sodium 2-amino-3-(4-bromobenzylidene)phenylacetate. 3. Tris / dihydrate, etc., preferably include sodium 2-amino-3-(4-bromobenzylidene) phenylacetate. Tri/dihydrate.

The eyedropting agent of the present invention is stable for a long period of time, and can suppress the occurrence of precipitates due to the coexistence of bromfenac with other components, and can maintain the concentration of bromfenac high for a long period of time. Therefore, the eyedrop agent of the present invention can stably exhibit effects such as pharmacological effects as a therapeutic agent for coping with symptoms of ocular inflammation such as conjunctivitis, allergic conjunctivitis, or orbital inflammation.

The eyedrop agent of the present invention can exhibit excellent antiseptic efficacy for a long period of time and even exhibits preservation efficiency, and is suitable for storage in a multi-dose container, for example, because there is no dripping of eye drops and the eye container does not cause cracks.

Eyedrop antiseptic effect maintenance method

The present invention also provides a method for maintaining the antiseptic efficacy of the following eye drops (also referred to as "eyedrop agent preservative efficacy maintenance method"), which contains 0.01 to 1.0% (w/v) of 2-amino group. -3 -(4-bromobenzylidene)phenylacetic acid or a salt thereof, and substantially does not contain a cationic preservative and a nonionic surfactant.

The method comprises the steps of: containing 215-360 mM of boric acid ions and 0.001-0.15% (w/v) of sodium edetate, and setting the osmotic pressure ratio of the eye drops to 0.8-1.3. According to this method, even if it is an ophthalmic agent which does not contain a cationic preservative and a nonionic surfactant substantially, it can exhibit excellent antiseptic effect for a long period of time, and the antiseptic effect can be exhibited, and the preservation effect can be exhibited for a long period of time.

In the method for maintaining the anti-corrosion efficacy of the ophthalmic agent, the description of the components in the ophthalmic agent of the present invention can be applied to the boric acid ion, the sodium edetate and the osmotic pressure ratio, including the preferred values thereof. Further, as an eye drop agent which maintains the antiseptic effect by the method, the description about the eye drop agent of the present invention described above can be applied.

[Examples]

The formulation examples and test results are disclosed below, but these are not intended to limit the scope of the present invention in order to better understand the present invention.

(1) Formulation examples

Each of the preparations of Examples 1 to 14 and Comparative Examples 1 to 5 was prepared as shown below. The composition of each formulation is summarized in Tables 1-3. In Tables 1-3, "%" means %(w/v).

Example 1

0.9 g of boric acid, 0.7 g of borax, 60 mL of purified water, and 20 mL of 0.5% sodium chloride/0.1% sodium edetate aqueous solution were added, and the mixture was sufficiently stirred. 2. 2-Amino-3-(4-bromobenzylidene) phenylacetate was added to the solution. 0.1 g of tri/dihydrate (hereinafter, also referred to as Compound A) was sufficiently stirred. Add dilute hydrochloric acid and sodium hydroxide test solution, set the pH to about 8.0, add appropriate amount of pure Water was made and the total amount was set to 100 mL.

Example 2

0.9 g of boric acid, 0.7 g of borax, 60 mL of purified water, and 20 mL of 0.5% sodium chloride/0.1% sodium edetate aqueous solution were added, and the mixture was sufficiently stirred. To the solution, 0.08 g of sodium edetate hydrate and 0.1 g of a compound A were added, and the mixture was sufficiently stirred. After adding a diluted hydrochloric acid and sodium hydroxide test solution and setting the pH to about 8.0, an appropriate amount of purified water was added and the total amount was set to 100 mL.

Example 3

Will be 2.2% boric acid. 85 mL of a 2.2% borax aqueous solution, 50 mL of a 0.6% sodium chloride/0.4% potassium chloride aqueous solution, and 4.25 mL of a 0.8% sodium edetate hydrate aqueous solution were added to a beaker, and the mixture was sufficiently stirred. 0.2 g of the compound A was added to the solution, and the mixture was sufficiently stirred. After adding a diluted hydrochloric acid and sodium hydroxide test solution and setting the pH to about 8.0, an appropriate amount of purified water was added and the total amount was set to 200 mL.

Example 4

85 mL of a 2.2% boric acid/2.2% borax aqueous solution, 50 mL of a 0.6% sodium chloride/0.4% potassium chloride aqueous solution, and 4.25 mL of a 0.8% aqueous sodium edetate hydrate solution were added to a beaker, and the mixture was sufficiently stirred. 0.2 g of the compound A was added to the solution, and the mixture was sufficiently stirred. After adding a diluted hydrochloric acid and sodium hydroxide test solution and setting the pH to about 8.6, an appropriate amount of purified water was added and the total amount was set to 200 mL.

Example 5

1.1 g of boric acid, 0.9 g of borax, 60 mL of purified water, and 20 mL of 0.5% sodium chloride/0.1% sodium edetate aqueous solution were added, and the mixture was sufficiently stirred. 0.1 g of the compound A was added to the solution, and the mixture was sufficiently stirred. After adding a diluted hydrochloric acid and sodium hydroxide test solution and setting the pH to about 8.0, an appropriate amount of purified water was added and the total amount was set to 100 mL.

Example 6

1.1 g of boric acid, 0.9 g of borax, 60 mL of purified water, and 20 mL of 0.5% sodium chloride/0.1% sodium edetate aqueous solution were added, and the mixture was sufficiently stirred. 0.1 g of the compound A was added to the solution, and the mixture was sufficiently stirred. After adding a diluted hydrochloric acid and sodium hydroxide test solution and setting the pH to about 8.3, an appropriate amount of purified water was added and the total amount was set to 100 mL.

Example 7

160 mL of an aqueous solution of 1.4% boric acid, 1.4% borax, 0.13% sodium chloride, 0.03% sodium edetate hydrate was added to the beaker. 0.3 g of sodium chloride and 0.2 g of potassium chloride were added, and the mixture was sufficiently stirred. 0.2 g of the compound A was added to the solution, and the mixture was sufficiently stirred. After adding a diluted hydrochloric acid and sodium hydroxide test solution and setting the pH to about 8.3, an appropriate amount of purified water was added and the total amount was set to 200 mL.

Example 8

1.3 g of boric acid, 1.0 g of borax, 60 mL of purified water, and 20 mL of 0.5% sodium chloride/0.1% sodium edetate aqueous solution were added, and the mixture was sufficiently stirred. 0.1 g of the compound A was added to the solution, and the mixture was sufficiently stirred. After adding a diluted hydrochloric acid and sodium hydroxide test solution and setting the pH to about 8.0, an appropriate amount of purified water was added and the total amount was set to 100 mL.

Example 9

80 mL of a solution of 1.6% boric acid, 1.3% borax, 0.03% sodium edetate hydrate, 0.13% sodium chloride and 0.13% compound A was added to the beaker. After adding a diluted hydrochloric acid and sodium hydroxide test solution and setting the pH to about 8.3, an appropriate amount of purified water was added and the total amount was set to 100 mL.

Example 10

After 160 mL of purified water was added to the beaker, 2.2 g of boric acid, 2.2 g of borax, 0.4 g of sodium chloride, and 0.04 g of sodium edetate hydrate were added, and the mixture was sufficiently stirred. 0.1 g of the compound A was added to the solution, and the mixture was sufficiently stirred. Add dilute hydrochloric acid or sodium hydroxide test solution, set the pH to about 8.3, An appropriate amount of purified water was added and the total amount was set to 200 mL.

Example 11

After 160 mL of purified water was added to the beaker, 2.2 g of boric acid, 2.2 g of borax, 0.4 g of sodium chloride, and 0.01 g of sodium edetate hydrate were added, and the mixture was sufficiently stirred. 0.2 g of the compound A was added to the solution, and the mixture was sufficiently stirred. After adding a diluted hydrochloric acid or sodium hydroxide test solution and setting the pH to about 8.3, an appropriate amount of purified water was added and the total amount was set to 200 mL.

Example 12

After 160 mL of purified water was added to the beaker, 2.2 g of boric acid, 2.2 g of borax, and 0.04 g of sodium edetate hydrate were added, and the mixture was sufficiently stirred. 0.2 g of the compound A was added to the solution, and the mixture was sufficiently stirred. After adding a diluted hydrochloric acid or sodium hydroxide test solution and setting the pH to about 8.3, an appropriate amount of purified water was added and the total amount was set to 200 mL.

Example 13

After 160 mL of purified water was added to the beaker, 2.4 g of boric acid, 2.0 g of borax, 0.4 g of sodium chloride, and 0.04 g of sodium edetate hydrate were added, and the mixture was sufficiently stirred. 0.2 g of the compound A was added to the solution, and the mixture was sufficiently stirred. After adding a diluted hydrochloric acid or sodium hydroxide test solution and setting the pH to about 7.8, an appropriate amount of purified water was added and the total amount was set to 200 mL.

Example 14

After 160 mL of purified water was added to the beaker, 2.6 g of boric acid, 2.8 g of borax, and 0.1 g of sodium edetate were added, and the mixture was sufficiently stirred. 0.2 g of the compound A was added to the solution, and the mixture was sufficiently stirred. After adding a diluted hydrochloric acid or sodium hydroxide test solution and setting the pH to about 8.3, an appropriate amount of purified water was added and the total amount was set to 200 mL.

Comparative example 1

After 50 mL of purified water was added to the beaker, 0.7 g of boric acid, 1.0 g of borax, and 0.2 g of sodium chloride were added, and the mixture was sufficiently stirred. 2 mL of a 1.0% sodium edetate hydrate solution and 0.1 g of a compound A were added to the solution, and the mixture was sufficiently stirred. After adding a diluted hydrochloric acid and sodium hydroxide test solution and setting the pH to about 8.3, an appropriate amount of purified water was added and the total amount was set to 100 mL.

Comparative example 2

After 50 mL of purified water was added to the beaker, 0.7 g of boric acid, 1.0 g of borax, and 0.2 g of sodium chloride were added, and the mixture was sufficiently stirred. To the solution, 5 mL of a 1.0% sodium edetate hydrate solution and 0.1 g of a compound A were added, and the mixture was sufficiently stirred. After adding a diluted hydrochloric acid and sodium hydroxide test solution and setting the pH to about 8.3, an appropriate amount of purified water was added and the total amount was set to 100 mL.

Comparative example 3

After 50 mL of purified water was added to the beaker, 0.7 g of boric acid, 1.0 g of borax, and 0.2 g of sodium chloride were added, and the mixture was sufficiently stirred. 0.1 g of the compound A was added to the solution, and the mixture was sufficiently stirred. After adding a diluted hydrochloric acid and sodium hydroxide test solution and setting the pH to about 8.3, an appropriate amount of purified water was added and the total amount was set to 100 mL.

Comparative example 4

After 160 mL of purified water was added to the beaker, 1.6 g of boric acid, 2.0 g of borax, and 0.4 g of sodium chloride were added, and the mixture was sufficiently stirred. 0.1 g of the compound A was added to the solution, and the mixture was sufficiently stirred. After adding a diluted hydrochloric acid or sodium hydroxide test solution and setting the pH to about 8.3, an appropriate amount of purified water was added and the total amount was set to 200 mL.

Comparative Example 5

After 160 mL of purified water was added to the beaker, 1.8 g of boric acid, 1.8 g of borax, and 0.4 g of sodium chloride were added, and the mixture was sufficiently stirred. 0.1 g of the compound A was added to the solution, and the mixture was sufficiently stirred. After adding a diluted hydrochloric acid or sodium hydroxide test solution and setting the pH to about 8.3, an appropriate amount of purified water was added and the total amount was set to 200 mL.

[Measurement of osmotic pressure and osmotic pressure ratio]

For each of the preparations obtained in Examples 1 to 14 and Comparative Examples 1 to 5, the osmotic pressure and the osmotic pressure were determined by the method described in the osmotic pressure measurement method (osmotic concentration measurement method) of the Japanese Pharmacopoeia Sixteenth Revision. The ratio is measured. The results are shown in Tables 1 to 3.

(2) Preservation effectiveness test

The storage efficacy test was carried out using the respective preparations obtained in Examples 1, 3 to 5, and 7 to 14 and Comparative Examples 1 to 5 as follows.

[Method of operation]

Test and judge according to the reference information of the 16th revised edition of the Japanese Pharmacopoeia and the preservation efficacy test method.

The five strains shown in Tables 5 to 7 were inoculated on the surface of agar slant medium and precultured. As a pre-culture agar medium, use soybeans in the case of bacteria. Casein. Hydrolyzed agar medium, used in the case of fungi. Dextrose agar medium. In the case of bacteria, pre-cultured at 30-35 ° C for 18-24 hours, Candida albicans was pre-incubated at 20-25 ° C for 44-52 hours, and Aspergillus brasiliensis was pre-treated at 20-25 ° C. Incubate for 1 week or until sufficient spores are formed. The samples of Examples 1 to 9 and Comparative Examples 1 to 3 were dispensed into 5 sterilized PE containers, and the pre-cultured test bacteria shown in the following Tables 5 to 7 were prepared to be 10 ⁵ to 10 The mixed sample was inoculated in a manner of ⁶ cells/mL, and then stored at 20 to 25 ° C for light shielding. Furthermore, the test bacteria were not mixed and each was inoculated separately to each sample. After storing for 2 weeks and 4 weeks from the start of storage, 1 mL of the liquid was sampled from each mixed sample, and the number of viable cells was measured. The test strains are described below.

Escherichia coli ATCC 8739

Pseudomonas aeruginosa ATCC 9027

Staphylococcus aureus ATCC 6538

Candida albicans ATCC 10231

Aspergillus brasiliensis ATCC 16404

[determination]

The determination of the effectiveness of preservation is in accordance with Table 4. When it satisfies the criterion of the judgment described in Table 4, it is judged that it has the preservation effect. When all the test strains have a storage efficiency, it is judged to have a storage efficiency (?), and it is considered that a sample having a bacteria which does not satisfy the above-mentioned criteria for the bacteria and fungi is considered to have insufficient preservation efficiency (?). The test results are shown in Tables 5-7.

[investigation]

All the test strains of the preparations of Examples 1, 3 to 5, and 7 to 14 each had a storage efficiency (?), but the boric acid ion concentration was 210 mM, Comparative Examples 1 to 3, and Comparative Example without sodium edetate. The test strains of 4 to 5 were not sufficiently effective (△).

(3) Storage stability test

Each of the preparations obtained in Examples 1, 2, 5, 6 and 8 was placed in a closed container and allowed to stand in a thermostat at 70 ° C for 8 days, thereby carrying out a storage stability test. After the passage of time, each preparation was placed at room temperature and cooled, and the residual ratio (% (w/v)) of bromfenac at 25 ° C and the osmotic pressure ratio were measured and the state of the solution was observed.

The residual rate of bromfenac was determined using UPLC manufactured by Waters Corporation. The column was made using Acquity HSS C18 SB (2.1 mM I.D. × 100 mM, particle diameter 1.8 μm) manufactured by Waters Co., Ltd., and maintained at a constant temperature of about 30 °C. Regarding the mobile phase, the acetonitrile and the 0.01% phosphoric acid solution were adjusted to pH 3.5 at a flow rate of 0.47 mL, and the gradient mode was used for 8 minutes. The sample is 2 μL It was injected with water diluted to 10 times and detected at a wavelength of 230 nm.

The measurement of the osmotic pressure ratio is carried out by the above method. The solution state was observed by visual observation.

The results are shown in Table 8.

[investigation]

Each of the formulations of Examples 1, 2, 5, 6 and 8 was clear and free of precipitates after storage at 70 ° C for 8 days.

Claims (7)

An eye drop agent comprising 0.01-1.0% (w/v) of 2-amino-3-(4-bromobenzylidene)phenylacetic acid or a salt thereof, 215-360 mM boric acid ion and 0.001-0.15% (w/v) sodium edetate, and substantially does not contain a cationic preservative and a nonionic surfactant, and the osmotic pressure ratio of the eyedrop is 0.8 to 1.3. An eye drop agent comprising 0.01-1.0% (w/v) of 2-amino-3-(4-bromobenzylidene)phenylacetic acid or a salt thereof, 215-360 mM boric acid ion and 0.001-0.15% (w/v) sodium edetate, and substantially free of cationic preservatives and nonionic surfactants, which meet the criteria for determination in the preservation efficacy test method of the Japanese Pharmacopoeia Sixteenth Revision. The ophthalmic agent according to claim 1 or 2, wherein the 2-amino-3-(4-bromobenzylidene)phenylacetic acid or a salt thereof is bromfenac sodium. An eye drop according to any one of claims 1 to 3, which further contains 0.01 to 0.5% (w/v) of sodium chloride. An eye drop agent according to any one of claims 1 to 4, which has a pH of from 7.8 to 8.6. An eye drop agent according to any one of claims 1 to 5, which is contained in a multi-dose type container. A method for maintaining the antiseptic effect of an eye drop agent is a method for maintaining the antiseptic effect of an eye drop agent containing 0.01 to 1.0% (w/v) of 2-amino-3-(4-) a bromobenzylidene-based phenylacetic acid or a salt thereof, and substantially free of a cationic preservative and a nonionic surfactant, the method comprising: The eyedrops are contained in an amount of 215 to 360 mM of boric acid ions and 0.001 to 0.15% (w/v) of sodium edetate, and the osmotic pressure ratio of the above eye drops is set to 0.8 to 1.3.